Natalie Davies and SSA-funded PhD student Merve Mollaahmetoglu discuss the potential of ketamine for treating substance use problems, and Natalie asks Merve about her experience of publishing peer-reviewed papers while a student.

Natalie: You published a systematic review about the effects of ketamine on a range of mental health, substance use, and eating disorders. Can you explain what ketamine is, what kinds of effects ketamine has, and why it might be useful as a treatment?

Merve: “Ketamine is known for its anaesthetic and analgesic properties. It was synthesised in 1962 as an alternative to an anaesthetic drug that had undesirable side effects. Then in the 1970s people started using ketamine as a recreational drug because, at lower doses, it can make you have out-of-body experiences, and time and space distortions.”

“Since the 1970s, there have been investigations into ketamine’s use as a part of treatment for psychiatric disorders. The most well-known study was from the Krupitsky’s group in Russia in the 1990s, and they used ketamine combined with aversive therapy or psychedelic therapy to treat people who had alcohol use disorders.”

Original article: Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. By Zach Walsh & Merve Mollaahmetoglu and colleagues Published in BJPsych Open (2022).

“The second wave of research was in the early 2000’s and it took a slightly different approach. Whereas the earlier research was more focused on the acute subjective effects of ketamine and trying to apply these therapeutically, the later research was interested in the neurobiological effects of ketamine, and the acute subjective effects were seen as more of a nuisance. In the earlier research, ketamine was also provided alongside psychological support, whereas in most of the modern research, ketamine tended to be administered on its own.”

“Another difference between these two waves of research was that the doses were a lot higher in the earlier research compared to the later research. This could be for many reasons, but it is worth mentioning that the acute subjective effects are dose-dependent. So, if you see those as side effects rather than something to be useful in therapy, then it might make more sense to use lower doses than the higher doses preferred in the earlier work.”

So, when you examined the evidence base for using ketamine in a therapeutic way, how was it being administered, and what were the kinds of doses used?

“There were a lot of differences across different disorders, and different studies of the same kinds of disorders. Some studies used intranasal or oral doses of ketamine, but most of the research in the systematic review examined the effects of an intravenous (IV) dose of ketamine, of between 0.5 and 0.8 mg/kg. And, most of the studies administered ketamine as a stand-alone treatment, rather than alongside a psychological treatment.”

The review identified 83 studies in total across the domains of treating eating disorders, mental health problems, and substance use problems, with 14 focusing on substance and alcohol use disorders. Could you give an overview of what you found or what was most interesting to you as a researcher relating to substance use?

“For substance use disorders, the systematic review indicated that ketamine was associated with short-term decreases in craving and in alcohol and drug consumption, and increases in abstinence. The part that was most interesting to me, and related most to my PhD, was about alcohol use disorders.”

“The early clinical trials in Russia found that abstinence rates from alcohol were around 65 to 70% at the one-year follow-up, which is really high. But there were some problems with this early research. People in the control group received conventional psychotherapy or aversive therapy without ketamine, and they did not receive a placebo. The researchers also often only followed up the ketamine treatment groups and not the control groups, which might have inflated the therapeutic benefits of ketamine. And, they did not ‘blind’ their patients and experimenters to the treatment conditions.”

There is also limited research about the acute effects of ketamine, such as the dissociative, spiritual, and mystical effects and how these might relate to the therapeutic outcomes

“To try to address some of the limitations of the earlier research, later studies have used random allocation, double-blinding, placebo control groups, and controlled for the amount of time that people spend with a therapist/staff member. But, the lack of effective blinding remains an issue even in modern randomised controlled trials of ketamine. The purpose of blinding is to ensure that participants’ and experimenters’ expectations about a given treatment don’t influence the treatment outcomes. But with ketamine’s unique subjective effects (e.g., dissociation, out of body experiences) it is likely that people will realise they are taking ketamine anyway, and this may confound the treatment effects.”

A study that wasn’t included in the review because it was published later, was from the Ketamine for the Reduction of Alcoholic Relapse (KARE) trial, and it used a similar dose of ketamine (0.8mg/kg), combined with mindfulness-based relapse prevention or alcohol education. The researchers found that there was a greater number of days abstinent from alcohol 6 months later in the ketamine group compared to the placebo group. They also found that the greatest effects were when ketamine was combined with psychotherapy compared to placebo combined with alcohol education.”

One of the concerns about using certain types of medication for treating substance use problems is the risk of them being diverted to the illicit drug market or being used for non-prescribed reasons. Did you find any evidence that this was a risk when ketamine was used in therapeutic context?

“That’s a really important question. In this review, none of the studies reported a transition to recreational use or self-medication. But, actually, not many of the studies recorded this, and even the ones that did record and report it, didn’t follow up on ketamine use in the long term.”

“In the KARE trial that I just mentioned, we interviewed 12 out of 48 of the participants who received ketamine as part of the trial. Only one of them said they had used ketamine recreationally, and this was not necessarily linked to the trial. So, overall there was no indication that there was excessive use or an addiction to ketamine in this trial, but obviously, this is something I think that we need to monitor systematically in the long term.”

What would you say are some of the challenges of researching ketamine, and what gaps in the research have you noted from doing this systematic review?

“This systematic review was really interesting in terms of bringing all the evidence together, but also showing that lots of questions remain unanswered.”

“One of the difficulties in summarising this research was the differences in measures across the different studies – for example, the different doses, number of doses, modes of administration, the different types of adjunct psychological therapies, and the frequency of treatments. It was wildly different across different studies, and we don’t quite yet know what is the most effective way of delivering ketamine. You know, what administration route is the best? What is the ideal dose? What is the best adjunctive therapy to combine with ketamine?”

This review indicated that ketamine has therapeutic effects across a variety of psychiatric disorders, but studies have required people to have a pure diagnosis with no comorbidities … which is not representative

“We are also lacking in research about the optimal circumstances for delivering ketamine treatment – such as the expectations and beliefs that people are bringing to the experience, but also the physical environment that the experience takes place in. We know that this can be really important in determining people’s experiences, and possibly the therapeutic outcomes. And, there is also limited research about the acute effects of ketamine, such as the dissociative, spiritual, and mystical effects and how these might relate to the therapeutic outcomes.”

“This review indicated that ketamine has therapeutic effects across a variety of psychiatric disorders, but studies have generally required people to have a pure diagnosis with no comorbidities and no other complications, which is not representative of the general psychiatric population, where comorbidities are the norm. This is not just the case for ketamine, but I think just generally for clinical trials, and means that treatments that are effective in clinical trials may prove to be less effective in the real world.”

Yes, it sounds like there are lots of questions left to be answered, and I guess that makes it an exciting time to be involved in the study of ketamine. That brings me on quite nicely to some questions I had about you being a PhD student and how you have managed to find the time to write and publish papers. You’re currently finalising your thesis*, but prior to that you were also doing your own research, helping to produce a podcast, and so on. How much of a priority have you made publishing throughout PhD?

“I guess for me, throughout the PhD, I’ve been able to publish by using what I would be writing up anyway for my thesis. So that has been an effective strategy for me because I can publish a couple of my chapters and put them into my thesis without a lot of changes. So actually, that has been a good way of doing it – writing my thesis and submitting journal articles as I go.”

“About making time for other things – I think right now, while I’m in the final stages of the PhD, I’m definitely making much less time for other things. But, in the first couple of years, I could be quite flexible with my time. And I actually really enjoyed having a bit of variety. You know, if I was getting stuck with writing a paper, I had something else to ‘productively procrastinate’ on – such as the PhD podcast.”

“I feel like all the other things that I’ve done have enriched my PhD experience. So I would definitely recommend people getting involved with things they’re interested in, especially at the earlier stages of the PhD. But I guess I would recommend trying to wind the workload down towards the end and prioritising writing up and finishing the thesis, as otherwise it can be a bit overwhelming.”

When you made the decision to write your first academic paper, what helped you get to the point of submitting it to a journal for peer review?

“It definitely went through a lot of revision. I think I’d written the first draft in March, and then I submitted in June or something like that. So, I actually did take quite a long time over it.”

“When I submitted my first paper I was genuinely terrified. And, I think it’s normal for people to feel like that. But, supervisors are important in that sense for advising you on where you can submit and whether it’s ready for submission and also getting support from maybe other people in your lab, or maybe more senior PhD students in your group.”

* Accurate at the time of the interview. Since then, Merve has completed writing up and successfully passed her viva!

Merve Mollaahmetoglu is an SSA-funded PhD student within the Psychopharmacology and Addiction Research Centre at the University of Exeter. Merve’s PhD research focuses on the role of ruminative thinking in initiating and maintaining alcohol use disorders and exploring rumination as a target of pharmacological treatment approaches, namely with ketamine. She has published papers in Psychopharmacology on the topic of effects of alcohol consumption on rumination, and in Frontiers in Psychology on experiences of participants taking part in a clinical trial of ketamine.

Conversation edited by Natalie Davies.

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